The preparations from the plant Cannabis sativa (marijuana) are well known to have therapeutic effect against various diseases. Their active component, cannabinoids, exerts a wide spectrum of central and peripheral actions, such as analgesia, anti-convulsion, anti-inflammation and alleviation of both intraocular pressure and emesis. Cannabinoids have also shown efficacy as immune modulators in animal models of neurological conditions, such as experimental allergic encephalomyelitis (EAE) and neuritis. Since cannabinoids furthermore have the ability to inhibit the growth of various types of cancer cells in culture, as well as to induce the regression of gliomas in laboratory animals, they are also potential anti-tumor agents.
The most active component of marijuana, Δ9-tetrahydrocannabinol (THC), is a prescribed drug e.g. for the relief of nausea associated with cancer chemotherapy. THC research has lead to the discovery of cannabinoid receptors. It has recently been hypothesised that lipid derivatives, so-called endocannabinoids, represent the naturally occurring endogenous ligands for these receptors.
The effects of THC and the major endocannabinoids, anandamide and 2-arachidonyl glycerol, are mediated by the activation of specific G-protein coupled receptors. To date two different cannabinoid receptors have been cloned from mammalian tissues, and these are denoted CB1 and CB2. The central and most of the peripheral effects of cannabinoids are the result of CB1 activation. This receptor is abundant in the central nervous system where it mediates cannabinoid psychoactivity. CB1 is also present in peripheral nerve terminals and in non-neuronal sites, such as the testis, uterus, eyes, vascular endothelium and immune cells. CB2 is predominantly present in peripheral tissues that are associated with immune functions, i.e. spleen, tonsils, B-cells and macrophages, whereas it is not detectable in neurons.
Receptor ligands that are selective for CB1 and/or CB2 could be useful therapeutic agents in the treatment of various pathological conditions, including nausea, pain and disorders related thereto. Since far from all patients experience adequate relief of symptoms with existing drugs against these conditions, there is still a need to discover novel therapeutic compounds.
The PCT application published as WO 02/085866 discloses compounds active as CB2 agonists and their use in the management of pain. Pain categories exemplified (pages 8-9) are chronic pain, such as chronic inflammatory pain, neuropathic pain, back pain, cancer pain and visceral pain, as well as acute pain. The compounds disclosed in WO 02/085866 (cf. the R6 moieties in particular) are different from those of the present invention.
Compounds of somewhat related, albeit different, structure compared to those of the present invention are disclosed e.g. in the Japanese publication JP 2002 201171 and the PCT application published as WO 91/18885.